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Human Papillomavirus EQA Programme 2014
(QCMD HPVDNA14)
Ed Schuuring
Pathology, UMCG, Groningen, NL
Scientific expert and advisor for QCMD HPV Program
Presentatie SKML-deelnemersvergadering
16 juni 2015
Potential conflicts of interest (2011-2015):
member of NVVP-CMDP-HPV-taakgroep
Scientific expert and advisor for QCMD HPV Program (2009-today)
Head of HPV-testing lab UMCG/Winschoten/Friesland (cobas HPV test)
Receipt of grants/research support: Hologic, QCMD, CTMM, MDXHealth/OncoMethylome
Receipt of honoraria or consultation fees: Hologic, Roche
Speaker’s fee: Hologic, Roche
Travel reimbursements: Hologic, QCMD, Abbott
The early detection of cervical cancer in scrapingpopulation-based screening programs worldwide
1) cytomorphology only
The classical approach
2) primary cytomorphology and HPV reflex testing
Presently used commonly (eg Dutch guidelines)
3) cytomorphology /HPV co-testing
Guideline in USA (Saslow 2012)
4) primary HPV testing and reflex cytomorphology
New guideline in NL starting in July 2016; interim guideline in USA 2015
5) primary HPV testing and reflex CINTEC, methylation,
hrHPV-typing and others
Presently validated
Normal cervix CIN III
HPV in scrapings of (pre)malignant cervical lesions
~4% high-risk HPV-positive ~85% high-risk HPV-positive
100% high-risk HPV-positive
Praktijkrichtlijn BVO cervixcytologie: indicatie HPV-onderzoek bij Pap2/3A1
Pap 197.1%
Retour BVO 5 jaar
Pap 2Pap 3A12.1%
Herhalen 6 maanden
+ HPV
Pap 170%
Pap 2Pap 3A125%
Pap 3A2>5%
HPV-
HPV+
HPV-49%
HPV+51%
Herhalen 12 maanden
GynaecoloogPap 3A2 >0,6%
Bulkmans, the Lancet, 2007Bais, Int J Cancer, 2005
Rebolj, Int J Cancer, 2007 J Eijsink
Analytical and clinical sensitivity of HPV-detection assays
Analytical sensitivity of PCR-based methods detecting
<10 HPV copies
Analytical sensitivity of PCR-based methods detecting
<10 HPV copies
Clinical sensitivity of HC2 is 5000 HPV copies
Clinical sensitivity of HC2 is 5000 HPV copies
Adapted from Snijders et al. Journal of Pathology 2003; 201:1-6
Clinical validated HPV-tests (in the Netherlands)Digene HC2 HPV test (Qiagen)
GP5+/GP6+ PCR EIA (Vumc/Qiagen)
Cobas 4800 HPV test (Roche)
Cervista hrHPV test (Hologic)
GenProbe-Aptima hrHPV assay (Hologic)
Abbott realtime HR HPV assay (Abbott)
Kwantitatieve multiplex RT HPV test (PON)
FDA-approved clinical HPV testsDigene HC2 HPV test (Qiagen)Cervista HPV HR test (Hologic) > internal controlCervista HPV 16/18 test (Hologic) > internal controlGenProbe-Aptima hrHPV assay (Hologic) > based on RNACobas 4800 HPV test (Roche) > HPV16/18 separate and internal control
Commercial HPV tests
• Hybrid Capture 2 Qiagen• Digene HPV genotyping RH kit Qiagen• Digene HPV genotyping LX kit, Qiagen • Roche Amplicor HPV Test• Roche Linear array HPV Genotyping test• Innogenetics INNO-LiPA HPV Genotyping test• NucliSens EasyQ HPV Biomerieux• Aptima Gen-Probe• Human Papilloma Virus reagents Third Wave• BIOPAP QTS HPV Kit Loxo• Reveal HPV Real-Time HPV Detection Kit GenoID• AID STD assay GenID• AID HPV screening kit GenID• AID HPV typing kit GenID• Linear ArrayExtra HPV Genotyping Kit Innogenetics• PCR Human Papillomavirus Detection Set Takara Mirus Bio• HPV DNA Chip Biomedlab• Array Papillomavirus Genomica• ProDect Chip HPV typing Bcs Biotech S.P.A• PapType Genera Biosystems• LCD Array HPV 3.5 Chipron• Seeplex HPV Genotyping Seegene• Viroactiv Virofem• HPV OncoTest Invirion Diagnostics• Genpoint Tm HPV test Dako-Oxoid• Abbott RealTime High Risk HPV Abbott• Luminex HPV Genotyping, Multimetrix/Progen • Greiner PapilloCheck HPV Screening • PreTect HPV Proofer Norchip• ………
Andere toepassingen voor HPV testen:
•Follow-up patienten behandeld voor CIN3•Profylactische vaccinatie•Therapeutische vaccinitie•Diagnose RRP (recurrent respiratory papillomatosis)•Klonale verwantschap•… …
available HPV EQA platforms
1) QCMD HPVDNA:
• using established cell lines in LBC (~4 HPV types)
2) WHO HPV panel:
• Plasmid DNA spiked into cell line DNA (>30-45 types)
3) NEQAS UK:
• Patient samples (~4 samples) Fagan, JClinVirol2010
ISO17043:2010 accreditated
6th QCMD HPVDNA EQA
Primary goals:
•To assess the proficiency of laboratories in the detection of different high risk Human Papillomavirus (HPV) types
•To provide laboratories with an analytical performance based on the consensus qualitative results of all participants
•To provide feedback on the number and percentage of datasets reporting typing result
Secondary goal:
•To provide laboratories with information on clinical reporting based on the consensus qualitative results of all participants
QCMD 2014 Human Papillomavirus DNA EQA Programme (HPVDNA14)aims
QCMD 2014 EQA Programme report Nov 2014 QAV094130
• Door simulatie van klinische samples mbv “established” BMKH-
cellijnen in dunne-laag-cytologie
• Core samples: voor proficiency testing (rapportage performance)
• Educational samples: lastige, uitdagende monster ter lering
QCMD 2014 Human Papillomavirus DNA EQA Programme (HPVDNA14)composition EQA panel Human Papillomavirus 2014 EQA Programme
QCMD – QAV094130 – HPVDNA14
Internationale rondzending:
UMCG: Ed Schuuring (Scientific Advisory Board)
UMCG: Lorian Slagter-Menkema (preparation/validation)
UMCG: MD-cytology lab (cobas-HPV testing)
Reference-labs: UMCG and 3 others (?)
QCMD: Paul Wallace, Catherina di Lorenze
QCMD = Quality Control for Molecular Diagnostics (Scotland)
UMCG = CCKL(ISO15189) accreditated
QCMD 2014 EQA Programme report Nov 2014 QAV094130
QCMD 2014 Human Papillomavirus DNA EQA Programme (HPVDNA14)composition EQA panel
QCMD 2014 EQA Programme report Nov 2014 QAV094130
• 10 samples in PreservCyt• 4 core samples containing HPV16, 18, 45 or mix 16/18 in BSM using established cell lines• 2 core samples with BSM only as HPV-negative controls• viral load determined by both cobas and HC2 DNA testing
• 1 education sample with low viral HPV16 load (“clinical HPV-negative”)• 3 education samples with other HPV genotypes (determined by LIPA) (provided by PON)
• all samples pre-tested and confirmed in reference-labs by HC2 (2x) and cobas (2x)
QCMD 2014 Human Papillomavirus DNA EQA Programme (HPVDNA14)composition EQA panel
Primary goals using core samples:
•To assess the proficiency of laboratories in the detection of different high risk Human Papillomavirus (HPV) types
•To provide laboratories with an analytical performance based on the consensus qualitative results of all participants
•To provide feedback on the number and percentage of datasets reporting typing result
Secondary goal using educational samples:•To provide laboratories with information on clinical reporting based on the consensus qualitative results of all participants
QCMD 2014 Human Papillomavirus DNA EQA Programme (HPVDNA14)aims
QCMD 2014 EQA Programme report Nov 2014 QAV094130
QCMD 2009/10/11/12/13/14 Human Papillomavirus DNA EQA Programmeparticipation
HPVDNA09 HPVDNA10 HPVDNA11 HPVDNA12 HPVDNA13 HPVDNA14
Participants 108 155 167 171 194 228
Responders 98 136 149 153 176 203
Countries 26 26 27 31 34 37
Deelnemers in NL 14 21 27 26 31 30
Datasets:
- Analytical 113 44 88 91 194 226
- Clinical 113 77 133 144 137 157
- Genotyping 66 84 114 115 136 151
QCMD EQA Programme reports 2009-2014
Qualitive performance of all versus Dutch participantsQCMD-HPVDNA2014 (core samples only)
Performance of all participants
Performance of Dutch participants
83.3%
16.7%
0.0% 0.0% 0.0% 0.0% 0.0%
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
80.0%
90.0%
100.0%
6/6 5/6 4/6 3/6 2/6 1/6 0/6
Percentage of datasets
Number of core samples correct
Qualitive performance of all versus Dutch participantsQCMD-HPVDNA2014
Performance of all participants
Performance of Dutch participants
Qualitive performance of all versus Dutch participantsQCMD-HPVDNA2014
Performance of all participants
Performance of Dutch participants
Qualitive performance of all versus Dutch participantsQCMD-HPVDNA2014
Performance of all participants
Performance of Dutch participants
Qualitive performance of Dutch participantsQCMD-HPVDNA2014
Performance of Dutch participantsPrimary goals using core samples:
•To assess the proficiency of laboratories in the detection of different high risk Human Papillomavirus (HPV) types
•To provide laboratories with an analytical performance based on the consensus qualitative results of all participants
•To provide feedback on the number and percentage of datasets reporting typing result
Secondary goal using educational samples:•To provide laboratories with information on clinical reporting based on the consensus qualitative results of all participants
QCMD 2014 Human Papillomavirus DNA EQA Programme (HPVDNA14)aims
QCMD 2014 EQA Programme report Nov 2014 QAV094130
QCMD 2014 Human Papillomavirus DNA EQA Programme (HPVDNA14)composition EQA panel – educational cases
QCMD 2014 EQA Programme report Nov 2014 QAV094130
*
Performance of all participants
QCMD 2014 Human Papillomavirus DNA EQA Programme (HPVDNA14)composition EQA panel (clinical reporting)
QCMD 2014 EQA Programme report Nov 2014 QAV094130
In 2014 clinical performance is NOT reported individually:
•QCMD-report provides clinical reporting data separately•Samples HPV14-10 is considered clinically HPV-negative•For own interpretation only (educational case)•Sample does NOT represent determination of real clinical outcome•“Impossible” to prepare a clinical relevant sample (HPV-low-copy)
*
Clinical reporting of all versus Dutch participantsQCMD-HPVDNA2014
Performance of all participants
Performance of Dutch participants
Rapportage van lab dat clinical testing uitvoertperformance-score gebaseerd op core samples
Rapportage van lab dat clinical testing uitvoertperformance-score
QCMD 2014 Human Papillomavirus DNA EQA Programme (HPVDNA14)composition EQA panel (clinical reporting)
QCMD 2014 EQA Programme report Nov 2014 QAV094130
*
Clinical HPV-tests:
HC2: 1 pg/ml = ~5000 kopieën
Abbott: = ~5000 kopieën
Cobas = ~300 kopieën (afhankelijk van HPV-type)
Pre-test threshold van klinisch-relevante HPV assays
Dus eigenlijk kunnen we geen panel definiëren met een
klinische threshold omdat HC2 niet meer de standaard is
Qualitive performance of all versus Dutch participantsQCMD-HPVDNA2014 (core samples only)
83.3%
16.7%
0.0% 0.0% 0.0% 0.0% 0.0%
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
80.0%
90.0%
100.0%
6/6 5/6 4/6 3/6 2/6 1/6 0/6
Percentage of datasets
Number of core samples correct
2014 2013 2012
NL
allallall
NLNL
Vanaf 2013 alleen toetsing performance van analytische interpretatie
Educatief samples alleen als aparte reportage (eigen interpretatie op basis van performance van andere met vergelijkbare testen)
Vanaf 2015 tabel bij individual reporting cores en educational samples apart
Kleinere panels en meer rondzendingen/jaar (>2016)
Andere matrices (nu een pilot SurePath)
Ontwikkelen van referentie/calibratie-sets (pilot 2015)
QCMD HPV testen vanaf 2015 (planning)
Dank voor uw aandacht
Vragen ?
e.schuuring@umcg.nl
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